Modular control of vertebrate axis segmentation in time and space
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Ali Seleit
PROVIDER: S-SCDT-10_1038-S44318-024-00186-2 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Rhythmic and sequential subdivision of the elongating vertebrate embryonic body axis into morphological somites is controlled by an oscillating multicellular genetic network termed the segmentation clock. This clock operates in the presomitic mesoderm (PSM), generating dynamic stripe patterns of oscillatory gene-expression across the field of PSM cells. How these spatial patterns, the clock's collective period, and the underlying cellular-level interactions are related is not understood. A theory encompassing temporal and spatial domains of local and collective aspects of the system is essential to tackle these questions. Our delayed coupling theory achieves this by representing the PSM as an array of phase oscillators, combining four key elements: a frequency profile of oscillators slowing across the PSM; coupling between neighboring oscillators; delay in coupling; and a moving boundary describing embryonic axis elongation. This theory predicts that the segmentation clock's collective period depends on delayed coupling. We derive an expression for pattern wavelength across the PSM and show how this can be used to fit dynamic wildtype gene-expression patterns, revealing the quantitative values of parameters controlling spatial and temporal organization of the oscillators in the system. Our theory can be used to analyze experimental perturbations, thereby identifying roles of genes involved in segmentation.
| S-EPMC2689616 | biostudies-literature
Project description: Not available
| S-BSST1653 | biostudies-other
Project description:Taming cell-to-cell variability in gene expression is critical for precise pattern formation during embryonic development. To investigate the source and buffering mechanism of expression variability, we studied a biological clock, the vertebrate segmentation clock, controlling the precise spatiotemporal patterning of the vertebral column. By counting single transcripts of segmentation clock genes in zebrafish, we show that clock genes have low RNA amplitudes and expression variability is primarily driven by gene extrinsic sources, which is suppressed by Notch signaling. We further show that expression noise surprisingly increases from the posterior progenitor zone to the anterior segmentation and differentiation zone. Our computational model reproduces the spatial noise profile by incorporating spatially increasing time delays in gene expression. Our results, suggesting that expression variability is controlled by the balance of time delays and cell signaling in a vertebrate tissue, will shed light on the accuracy of natural clocks in multi-cellular systems and inspire engineering of robust synthetic oscillators.
| S-EPMC5989725 | biostudies-literature
Project description:Synovial joints are crucial for support and locomotion in vertebrates, and are the frequent site of serious skeletal defects and degenerative diseases in humans. Growth and differentiation factor 5 (Gdf5) is one of the earliest markers of joint formation, is required for normal joint development in both mice and humans, and has been genetically linked to risk of common osteoarthritis in Eurasian populations. Here, we systematically survey the mouse Gdf5 gene for regulatory elements controlling expression in synovial joints. We identify separate regions of the locus that control expression in axial tissues, in proximal versus distal joints in the limbs, and in remarkably specific sub-sets of composite joints like the elbow. Predicted transcription factor binding sites within Gdf5 regulatory enhancers are required for expression in particular joints. The multiple enhancers that control Gdf5 expression in different joints are distributed over a hundred kilobases of DNA, including regions both upstream and downstream of Gdf5 coding exons. Functional rescue tests in mice confirm that the large flanking regions are required to restore normal joint formation and patterning. Orthologs of these enhancers are located throughout the large genomic region previously associated with common osteoarthritis risk in humans. The large array of modular enhancers for Gdf5 provide a new foundation for studying the spatial specificity of joint patterning in vertebrates, as well as new candidates for regulatory regions that may also influence osteoarthritis risk in human populations.
| S-EPMC5130176 | biostudies-literature
Project description:Shaping embryonic tissues into their functional morphologies requires cells to control the physical state of the tissue in space and time. While regional variations in cellular forces or cell proliferation have been typically assumed to be the main physical factors controlling tissue morphogenesis, recent experiments have revealed that spatial variations in the tissue physical (fluid/solid) state play a key role in shaping embryonic tissues. Here we theoretically study how the regional control of fluid and solid tissue states guides morphogenetic flows to shape the extending vertebrate body axis. Our results show that both the existence of a fluid-to-solid tissue transition along the anteroposterior axis and the tissue surface tension determine the shape of the tissue and its ability to elongate unidirectionally, with large tissue tensions preventing unidirectional elongation and promoting blob-like tissue expansions. We predict both the tissue morphogenetic flows and stresses that enable unidirectional axis elongation. Our results show the existence of a sharp transition in the structure of morphogenetic flows, from a flow with no vortices to a flow with two counter-rotating vortices, caused by a transition in the number and location of topological defects in the flow field. Finally, comparing the theoretical predictions to quantitative measurements of both tissue flows and shape during zebrafish body axis elongation, we show that the observed morphogenetic events can be explained by the existence of a fluid-to-solid tissue transition along the anteroposterior axis. These results highlight the role of spatiotemporally-controlled fluid-to-solid transitions in the tissue state as a physical mechanism of embryonic morphogenesis.
| S-EPMC8060277 | biostudies-literature
Project description:During embryonic development, the timing of events at the cellular level must be coordinated across multiple length scales to ensure the formation of a well-proportioned body plan. This is clear during somitogenesis, where progenitors must be allocated to the axis over time whilst maintaining a progenitor population for continued elaboration of the body plan. However, the relative importance of intrinsic and extrinsic signals in timing progenitor addition at the single-cell level is not yet understood. Heterochronic grafts from older to younger embryos have suggested a level of intrinsic timing whereby later staged cells contribute to more posterior portions of the axis. To determine the precise step at which cells are delayed, we performed single-cell transcriptomic analysis on heterochronic grafts of somite progenitors in the chicken embryo. This revealed a previously undescribed cell state within which heterochronic grafted cells are stalled. The delayed exit of older cells from this state correlates with expression of posterior Hox genes. Using grafting and explant culture, we find that both Hox gene expression and the migratory capabilities of progenitor populations are intrinsically regulated at the population level. However, by grafting varied sizes of tissue, we find that small heterochronic grafts disperse more readily and contribute to more anterior portions of the body axis while still maintaining Hox gene expression. This enhanced dispersion is not replicated in explant culture, suggesting that it is a consequence of interaction between host and donor tissue and thus extrinsic to the donor tissue. Therefore, we demonstrate that the timing of cell dispersion and resulting axis contribution is impacted by a combination of both intrinsic and extrinsic cues.
| S-EPMC10834026 | biostudies-literature
Project description:One of the most striking features of the human vertebral column is its periodic organization along the anterior-posterior axis. This pattern is established when segments of vertebrates, called somites, bud off at a defined pace from the anterior tip of the embryo's presomitic mesoderm (PSM). To trigger this rhythmic production of somites, three major signaling pathways--Notch, Wnt/β-catenin, and fibroblast growth factor (FGF)--integrate into a molecular network that generates a traveling wave of gene expression along the embryonic axis, called the "segmentation clock." Recent systems approaches have begun identifying specific signaling circuits within the network that set the pace of the oscillations, synchronize gene expression cycles in neighboring cells, and contribute to the robustness and bilateral symmetry of somite formation. These findings establish a new model for vertebrate segmentation and provide a conceptual framework to explain human diseases of the spine, such as congenital scoliosis.
| S-EPMC3164975 | biostudies-literature
Project description:The modular control hypothesis suggests that motor commands are built from precoded modules whose specific combined recruitment can allow the performance of virtually any motor task. Despite considerable experimental support, this hypothesis remains tentative as classical findings of reduced dimensionality in muscle activity may also result from other constraints (biomechanical couplings, data averaging or low dimensionality of motor tasks). Here we assessed the effectiveness of modularity in describing muscle activity in a comprehensive experiment comprising 72 distinct point-to-point whole-body movements during which the activity of 30 muscles was recorded. To identify invariant modules of a temporal and spatial nature, we used a space-by-time decomposition of muscle activity that has been shown to encompass classical modularity models. To examine the decompositions, we focused not only on the amount of variance they explained but also on whether the task performed on each trial could be decoded from the single-trial activations of modules. For the sake of comparison, we confronted these scores to the scores obtained from alternative non-modular descriptions of the muscle data. We found that the space-by-time decomposition was effective in terms of data approximation and task discrimination at comparable reduction of dimensionality. These findings show that few spatial and temporal modules give a compact yet approximate representation of muscle patterns carrying nearly all task-relevant information for a variety of whole-body reaching movements.
| S-EPMC5891645 | biostudies-literature
Project description:Cis-regulatory elements control gene expression in time and space and their disruption can lead to pathologies. Reporter assays allow the functional validation of enhancers and other regulatory elements, and transgenic mice provide a powerful tool to study gene regulation in vivo. However, these experiments are time-consuming and inefficient. Here, we increase the throughput of transgenic reporter assays by using a piggyBac transposon-based system, and use it to decode the regulatory landscape of atrial fibrillation, a prevalent cardiac arrhythmia. We systematically interrogated ten human atrial fibrillation associated loci, finding five new cardiac-specific enhancers. We also connected novel genes to atrial fibrillation through genome editing and three-dimensional chromatin structure analysis. Of note, we identified a bivalent regulatory element in the second intron of the CAV1 gene at the 7q31 locus, differentially acting upon four genes. Our approach also detected negative regulatory elements such as an ubiquitous silencer in the 16q22 locus that regulates ZFHX3 and can outcompete heart enhancers. Our study characterizes the function of new genetic elements that might be of relevance for the better understanding of gene regulation in cardiac arrhythmias. Thus, we have established a new framework for the efficient dissection of the genetic contribution to common human diseases.
2024-10-31 | GSE180396 | GEO
Project description:BackgroundThe degree of conservation of gene expression between homologous organs largely remains an open question. Several recent studies reported some evidence in favor of such conservation. Most studies compute organs' similarity across all orthologous genes, whereas the expression level of many genes are not informative about organ specificity.ResultsHere, we use a modularization algorithm to overcome this limitation through the identification of inter-species co-modules of organs and genes. We identify such co-modules using mouse and human microarray expression data. They are functionally coherent both in terms of genes and of organs from both organisms. We show that a large proportion of genes belonging to the same co-module are orthologous between mouse and human. Moreover, their zebrafish orthologs also tend to be expressed in the corresponding homologous organs. Notable exceptions to the general pattern of conservation are the testis and the olfactory bulb. Interestingly, some co-modules consist of single organs, while others combine several functionally related organs. For instance, amygdala, cerebral cortex, hypothalamus and spinal cord form a clearly discernible unit of expression, both in mouse and human.ConclusionsOur study provides a new framework for comparative analysis which will be applicable also to other sets of large-scale phenotypic data collected across different species.
| S-EPMC3359279 | biostudies-literature